[The Effectiveness of Epidural Droperidol for Prophylaxis of Postoperative Nausea and Vomiting: A Comparative Study of Droperidol and Adrenaline].

BACKGROUND: Intravenous droperidol has strong evidence for antiemetic efficacy in high risk patients for prevention of postoperative nausea and vomiting (PONV). However it is not clear whether continuous epidural administration of doroperidol prevent PONV. It has been reported that epidural adrenaline decreases PONV; therefore we prospectively compared the effectiveness of epidural droperidol and adrenaline for prophylaxis of PONV. METHODS: Eighty-six patients were scheduled for abdominal gynecological surgery under general-epidural anesthesia in the study. Patients were randomly assigned to droperidol group or adrenaline group. We investigated the incidences of PONV, the frequency of using the antiemetics. RESULTS: There was no statistical difference between the groups. The incidences of PONV were 27.9% (doropeidol group) and 58.1% (adrenaline group), respectively (P = 0.0046). The frequency of the anti-emetics use were 18.6% and 41.9%, respectively (P = 0.0189). There was one patient who needed cancellation of continuous epidural administration for vomiting in adrenaline group, but no patient in doropeidol group. CONCLUSIONS: The results suggest that epidural droperidol effectively decreases PONV in high risk patients. However epidural adrenaline might be ineffective.

Valproate attenuates the development of morphine antinociceptive tolerance.

Morphine is a potent opioid analgesic. Repeated administration of morphine induces tolerance, thus reducing the effectiveness of analgesic treatment. Although some adjuvant analgesics can increase morphine analgesia, the precise molecular mechanism behind their effects remains unclear. Opioids bind to the mu opioid receptor (MOR). Morphine tolerance may be derived from alterations in the intracellular signal transduction after MOR activation. Chronic morphine treatment activates glycogen synthase kinase 3ß (GSK3ß), whose inhibition diminishes morphine tolerance. Valproate is widely prescribed as an anticonvulsant and a mood stabilizer for bipolar disorders because it increases the amount of γ-aminobutyric acid (GABA) in the central nervous system. Although the activation of GABAergic neurons may be responsible for the chief pharmacologic effect of valproate, recent studies have shown that valproate also suppresses GSK3ß activity. We examined the effect of valproate on the development of morphine antinociceptive tolerance in a mouse model of thermal injury. Mice were treated with morphine alone or with morphine and valproate twice daily for 5 days. The resulting antinociceptive effects were assessed using a hot plate test. While mice treated with morphine developed tolerance, co-administration of valproate attenuated the development of tolerance and impaired the activation of GSK3ß in mice brains. Valproate alone did not show analgesic effects; nevertheless, it functioned as an adjuvant analgesic to prevent the development of morphine tolerance. These results suggest that the modulation of GSK3ß activity by valproate may be useful and may play a role in the prevention of morphine tolerance.

BiP, an endoplasmic reticulum chaperone, modulates the development of morphine antinociceptive tolerance.

Morphine is a potent analgesic, but the molecular mechanism for tolerance formation after repeated use is not fully understood. Binding immunoglobulin protein (BiP) is an endoplasmic reticulum (ER) chaperone that is central to ER function. We examined knock-in mice expressing a mutant BiP with the retrieval sequence deleted in order to elucidate physiological processes that are sensitive to BiP functions. We tested the thermal antinociceptive effect of morphine in heterozygous mutant BiP mice in a hot plate test. Paw withdrawal latencies before and after a single administration of morphine were not significantly different between the wild-type and mutant BiP mice. Repeated morphine administration caused the development of morphine tolerance in the wild-type mice. The activation of glycogen synthase kinase 3b (GSK-3b) was associated with morphine tolerance, because an inhibitor of GSK-3ß prevented it. On the other hand, the mutant BiP mice showed less morphine tolerance, and the activation of GSK-3b was suppressed in their brain. These results suggest that BiP may play an important role in the development of morphine tolerance. Furthermore, we found that a chemical chaperone which improves ER protein folding capacity also attenuated the development of morphine tolerance in wild-type mice, suggesting a possible clinical application of chemical chaperones in preventing morphine tolerance.